3. Introduction
Almost all drugs are marketed as tablets, capsules or both.
Prior to the development of these major dosage forms, it is
essential that certain fundamental physical and chemical
properties of the drug molecule and other properties of the
drug powder are known. This information decides many of the
subsequent events and approaches in formulation development.
This first learning phase is known as pre formulation.
Before embarking on a formal programme of pre formulation
scientist must consider the following:
1. Available physicochemical data.
2. Anticipated dose.
3. Availability of stability indicating assay.
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4. Definition
Investigation of physicochemical properties of the new
drug compound that could affect drug performance
and development of an efficacious dosage form.
Pre formulation commences when a newly synthesized
drug shows a sufficient pharmacologic promise in
animal model to warrant evaluation in man.
Objective:
To generate useful information to the formulator to
design an optimum drug delivery system.
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5. Principle areas of pre formulation:
Bulk characterization:
a) Crystallinity and polymorphism
b) Hygroscopicity
c) Fine particle characterisation
d) Bulk density
e) Powder flow properties
Solubility analysis
a) Dissociation constant-pka
b) Ph solubility profile
c) Common ion effect
d) Thermal effects
e) Solubilisation
f) Partition coefficient
g) Dissolution
Stability analysis
a) Stability in toxicology formulations
b) Solution stability
c) Ph rate profile
d) Solid state stability
e) Bulk stability
f) Compatibility
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6. Goals of preformulation:
To establish the necessary physicochemical properties
of the drug substance.
To determine kinetic rate profile.
To establish physical characteristics.
To establish compatibility with other excipients.
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7. Partition coefficient
Definition:
Partition coefficient is a measure of a drugs
lipophilicity and an indication of its ability to cross the
cell membrane.
It is defined as the ratio of unionised drug distributed
between the organic and aqueous phases at
equilibrium.
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8. Partition coefficient
Importance:
For drug delivery, the lipophilic/hydrophilic balance
has been shown to be a contributing factor for the rate
and extent of drug absorption.
Since biological membranes are lipoidal in nature the
rate of drug transfer for passively absorbed drugs is
directly related to the lipophilicity of the molecule.
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9. Partition coefficient
Determination:
Various organic solvents are used in the determination of
partition coefficient include chloroform, ether, amyl acetate etc.
In formulation development the n-octanol/water partition
coefficient is commonly used.
For unionised drug-
P= concentration of drug in octanol/concentration of drug in
water
For ionised drug-
P= concentration of drug in octanol/(1-α) (concentration of drug
in water)
Lipophilic drugs have P value greater than 1 whereas hydrophilic
drugs have P value less than 1.
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10. Partition coefficient
Methods to determine partition coefficient:
Shake flask method.
Chromatographic method (HPTLC,TLC).
Counter current and filter probe method.
Applications:
Measure of the lipophilic character of the drug.
In the study of the ADME of a drug.
Extraction of dosage form from biological fluid.
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11. Dissociation constant:
Since majority of the drugs are either weakly acidic or weakly
basic, their solutions in water contain ionised and unionised
species.
In other words the drug undergoes dissociation in their aqueous
solutions. The extent of ionisation depends on the pH of the
solution. For example a weak acid will ionize mostly in alkaline
pH while a weakly basic will ionize in an acidic medium. The
unionised drug is more lipid soluble and thus readily absorbed.
Hence gastrointestinal absorption of a drug can be improved if
the extent of ionisation is reduced. The absorption of weakly
acidic or basic drugs can be influenced by the following factors:
1. pH at the site of absorption
2. Dissociation constant
3. Lipid solubility of unionised drugs
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12. Dissociation constant:
At a particular ph the relative concentration of
unionised and ionised species in a drug solution can
be estimated with the help of Henderson-hasselbalch
equation;
For acidic drugs- pH= pKa + log [ionised
drug]/[unionised drug]
For basic drugs- pH= pKa + log [unionised
drug]/[ionised drug]
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13. Dissociation constant
The contents of the stomach have pH ranging from 1-3.
weakly acidic drugs having a pKa value less than 4.3
were absorbed faster than those having pKa value
within 2-4.3, strongly acidic drugs were almost not
absorbed.
pH of intestinal fluid vary from 5-8.
In case of basic drugs the absorption is faster for those
having pKa values less than 8.5 than those having pKa
values between9-12.
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14. Dissociation constant
Thus for prediction of the site of absorption of weakly
acidic or basic drugs, knowledge of pKa is very
important.
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15. Dissociation constant
Drugs pKa value Ionization and site of absorption
Very weak acids
Eg; pentobarbital.
˃8
Unionized at all pH values.
Can be absorbed throughout any
region of the GIT.
Moderately weak acids
Eg; aspirin.
2.5-7.5
Unionized in gastric pH and
ionised at intestinal ph
Mostly absorbed from stomach.
Stronger acids
Eg;Disodiumchromoglycate.
˂2
Ionized at all pH values.
Poorly absorbed from GIT.
Stronger bases
Eg; guanethidine.
˃11
Ionized at all pH values
Poorly absorbed from GIT.
Moderately weak bases
Eg;codeine.
5-11
Ionised at gastric pH and
unionized at intestinal ph.
Mostly absorbed from intestine.
Very weak bases
Eg; theophylline.
˂5
Unionized at all pH values.
Can be absorbed throughout any
region of GIT. 15
16. Dissociation constant
Uses of Henderson hasselbalch equation:
To determine pka.
To predict solubility of any pH provided that the intrinsic
solubility (Co) and pka are known.
To facilitate selection of suitable salt forming compound.
To predict the solubility and pH properties of the salt.
Methods to determine pka:
Potentiometric method
Conductivity method
Dissolution rate method
Spectrophotometric method
Liquid-liquid partition method.
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17. Solubility
Amount of solute that can be dissolved into a standard
amount of solvent.
Example: At 25 ºC, the solubilities of the following
compounds are:
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Compound Solubility
NaCl 5.47 M
Sugar 6.00 M
Magnessium Hydroxide 0.0017 M
Carbondioxode 0.26 M
Oxygen 0.0016 M
18. Solubility
Significance of solubility:
1. Increased bioavailability: Any drug having solubility
less than 10mg/mL in physiologic pH range (pH 1 to
7) will produce bio absorption problem. A solubility
less than 1 mg/ml require salt formation of the drug
for better bioavailability.
2. Griseofulvin-orally the absorption is very less.
3. Taste masking: Eg; Chloramphenicol palmitate.
4. Reducing degradation in the GIT: Eg; erythromycin
estolate.
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19. Solubility
Intrinsic solubility of a drug (S0):
This is the fundamental solubility of a drug when it is completely unionized.
For a weak acid the intrinsic solubility is the solubility of the drug determined in
a strongly acidic solution.
For a weak base the intrinsic solubility is the solubility of the drug determined in
a strongly alkaline solution.
For a non-ionic molecule there will be no measurable change in the solubility in
either acidic or alkaline solution.
In case of weak acid and weak base the solubility can be manipulated by
changing the pH of the solution.
In case of non-ionisable molecules the solubility can be manipulated either by
changing the solvent, or by addition of co-solvent or by complexation.
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21. Solubility
Factors Affecting Solubility:
1. Intermolecular Forces
When attractions between solute molecules and solvent
molecules are strong, solutions are able to form. Solute
molecules are surrounded by solvent molecules. (Solvent
cage)“Like dissolves like”
Polar substances dissolve polar substances.
Nonpolar substances dissolve nonpolar substances.
Ionic (electrolytic) solutions.
2.Temperature
3. Pressure Effects On Solubility.
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22. Solubility
Approaches of increasing the solubility of
drugs:
1. By changing the pH of the solution.
2. By changing the solvent
Eg. Phenobarbital.
3. By changing the polymorphs.
Hydrates < Anhydrous < Solvates
4. By adding a suitable surfactant:
Eg-Sodium lauryl sulphate
5.By complexation:
Eg-Caffeine increases the solubility of benzoic acid by forming a
water-soluble complex. Solubility of para-aminobenzoic acid
(PABA) can be increased by complexing with caffeine.
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23. Solubility
Approaches of decreasing the solubility of drugs:
1.By esterification:
The solubility of chloramphenicol can be decrease by forming its ester
with palmitic acid.
2.By coating with polymers:
Drug particles may be coated with ethylcellulose to retard its water
solubility. Cellulose acetate phthalate (CAP),
hydroxypropylmethylcellulose phthalate (HPMCP) etc. polymers
reduce the solubility of drug particles in the acid medium of stomach.
3.By changing the polymorph:
Stable polymorphs have lower aqueous solubility than the metastable
forms. So by changing the condition of crystallization stable
polymorphs may be produced.
4.By selecting the hydrated forms:
Anhydrous ampicillin has greater water solubility than ampicillin-
trihydrate.
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24. Solubility
Importance of solubility:
Solubility is one of the most critical preformulation
properties that have a significant impact on
performance of a molecule. Solubility and
permeability form the backbone of Biopharmaceutics
Classification System (BCS) that provides scientific
framework for designing of drug delivery systems and
many regulatory decisions.
Solubility and Oral Absorption
Solubility and Formulation Development
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25. Conclusion:
Preformulation studies on a new drug molecule
provide useful information for subsequent formulation
of a physicochemically stable and biopharmaceutically
suitable dosage form.
Determination of solubility, partition coefficient and
dissociation constant are extremely important in
deciding a particular formulation for a drug.
Absorption of a drug ultimately depends on these
three parameters.
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26. Reference
Lachman, Leon, and Herbert A Liebermann. The Theory
and Practice Of Industrial Pharmacy. New Delhi: CBS
Publishers & Distributors Pvt. Ltd., 2012.
Tripathi, D.K. Industrial Pharmacy, A Comprehensive
Approach. Giriraj lane, Sultan Bazar,
Haydrabad.:PharmaMed Press, 2015.
Aulton, Michael E. Aulton's Pharmaceutics. Edinburgh:
Churchill Livingstone, 2007.
Academia.edu. CHAPTER – 1 Preformulation Studies
[Internet]. 2015 [cited 11 November 2015]. Available from:
http://www.academia.edu/7720904/CHAPTER_1_Preform
ulation _Studies
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